A. Field of the Invention
The invention relates to the use of nutrient combinations to prevent or reduce potential adverse effects from administration of androgenic testosterone precursors to humans and other mammals Specifically, the invention relates to co-administration of androgenic testosterone precursors such as pregnenolone, androstenediols, norandrostenediols, norandrostenedione, androstenedione or dehydroepiandrosterone in combination with natural products which inhibit estrogen effects in liver, adipose, prostate, ovarian, uterine, breast and other estrogen-responsive tissues, and substances which inhibit the production of dihydrotestosterone in prostate tissue.
B. Description of Related Art
Androstenedione (.DELTA..sup.4 -androstene-3,17-dione) is an adrenal steroid hormone. Pregnenolone is a precursor for dehydroepiandrosterone. Dehydroepiandrosterone (DHEA) is a precursor of androstenedione. Androstenedione is a direct precursor of estrone and testosterone in target tissues that possess the appropriate receptors and enzymes. Androstenediols are direct precursors for testosterone after oral administration in adult humans (unpublished data). 19-Norandrostenedione is a precursor for 19-nortestosterone, which has anabolic actions similar to testosterone, with less androgenic actions. 19-Norandrostenedione is a potential precursor for estrone. Testosterone is important for the development and maintenance of male sexual organs and characteristics, behavioral effects, anabolic (growth-promoting) actions, and metabolic effects for all tissues, especially muscles, liver and kidney. (Kutsky, R. J., Handbook of Vitamins, Minerals and Hormones, 2.sup.nd ed., Van Nostrand Reinhold Company, New York, 1981). Estrogens are essential for the development and maintenance of female reproductive organs and characteristics, pregnancy, and metabolic effects for all tissues (Kutsky, 1981).
Androstenedione levels in tissues, including skeletal muscle, of men and women decrease significantly with age. (Deslypere, J. P. and Vermeulen, A., Influence of age on steroid concentrations in skin and striated muscle in women and in cardiac muscle and lung tissue in men, J. Clin. Endocrinol. Metab. 61:648-653 (1985)). Since muscle wasting is associated with aging, these findings suggest that the loss of androstenedione is involved in muscle wasting. The corollary that androstenedione administration would maintain muscle mass is enticing, but has not been studied yet. Nevertheless, the data support an anabolic effect of androstenedione on muscle tissue in both men and women, with more effectiveness in men.
Blood levels of androstenedione decrease in some young men during prolonged, intense exercise. This decrease is thought to impede performance improvements. For example, serum androstenedione levels declined as weightlifting intensity increased in young men. (Alen et al., Responses of serum androgenic-anabolic and catabolic hormones to prolonged strength training, Int. J Sports Med. 9:229-233 (1988)). While androstenedione and other androgens were decreased, serum testosterone was maintained, which suggests that androstenedione provides precursors for synthesis of testosterone by muscle. Other indicators of over-training were more apparent as androstenedione levels decreased. Thus, androstenedione supplementation to young men engaged in vigorous weight training may help prevent androstenedione deficiency, and maintain anabolic responses to weight training.
To counteract this decrease in androstenedione levels, athletes have taken androstenedione orally, nasally or intravenously to increase testosterone levels. Empirical research supports the link between the administration of androstenedione and increases in testosterone levels. For example, oral and nasal administration of androstenedione to women increases serum testosterone levels. (Maresh, V. B. and Greenblatt, R. B., The in vivo conversion of dehydroepiandrosterone and androstenedione to testosterone in the human. Acta Endocrinol. 41:400-406 (1962); Mattern, C. and Hacker, R., European Patent Application No. 97-13 0639077 (1977)). Furthermore, androstenedione is converted into testosterone in muscle and adipose tissue in humans after intravenous administration. (Belisle et al, Metabolism of androstenedione in human pregnancy: use of constant infusion of unlabeled steroid to assess its metabolic clearance rate, its production rate, and its conversion into androgens and estrogens, Am. J. Obstet. Gynecol. 136: 1030-1035 (1980); Longcope, C. and Fineberg, S. E., Production and metabolism of dihydrotestosterone in peripheral tissues, J. Steroid Biochem. 23:415-419 (1985)). (This reference, and all the other references in this and subsequent sections, are incorporated by reference in their entirety.) These data have generated interest in androgenic testosterone precursors as ergogenic aids for improving anabolism in exercising persons, especially weight lifters and bodybuilders. Dietary supplement products containing androstenedione, androstenediols, norandrostenedione and norandrostenediols alone or in combination with other ingredients have appeared on the market recently.
Evidence has accumulated that suggests androstenedione excess is not benign. Androstenedione affects hormonally responsive target tissue in males and females. Androstenedione administration may cause overproduction of estradiol from estrone, and dihydrotestosterone (DHT) from testosterone. Estradiol and DHT account for most of the hormonal effects of estrogens and testosterone in target tissues. For example, long-term treatment of dogs and monkeys with androstenedione causes prostate enlargement and temporary shrinkage of testicles. While dogs are more sensitive to estrogens than humans, side effects may also occur in humans. Such side effects may include breast and prostatic cancer, benign prostatic hyperplasia, and hirsutism or acne in women. Since DHEA is a metabolic precursor of androstenedione, DHEA administration may also be associated with harmful side effects. Thus, androstenedione and DHEA administration should be carefully monitored to provide the desired anabolic effects without causing harmful side effects.
There is insufficient evidence to assess side effects from norandrostenediols or norandrostenedione from animal or human scientific literature. However, the known metabolic pathways of these prohormones indicate that estrone, in amounts equivalent to those formed by androstenedione or testosterone, can be formed from nor- analogs of androstenedione and testosterone (Raeside, J. I., Renaud, R. L., and Friendship, R. M., Aromatization of 19-norandrogens by porcine Leydig cells. J Steroid Biochem. 32(5):729-735 (1989)). These results indicate that the potential for unwanted side effects with nor-prohormones may be equivalent to that for androstenedione and testosterone.
Thus, there is a need for a composition and method for minimizing or preventing unwanted side effects associated with the administration of androgenic testosterone precursors in humans. In particular, there is a need for a composition and method which maintains androgenic testosterone precursor levels while minimizing or eliminating the effects of estrogen and DHT excess.